The need to treat debilitating bone disorders, such as osteoporosis, has led to extensive research on the mechanism and regulation of continuous bone formation and resorption. In particular, an appropriate balance of osteoblasts, which function to form bone tissue, and osteoclasts, which function to resorb bone tissue, is required to maintain the structural integrity and proper functioning of the skeleton in spite of continuous metabolism. Any changes in this balance of metabolism, such as an increased bone resorption (either absolute, or an increase via decreased bone formation relative to bone resorption) can lead bone diseases or disorders. One of the most common diseases resulting from this imbalance is osteoporosis, which is characterized by a decrease in bone mass and deterioration in skeletal micro-architecture leading to an increased fragility and susceptibility to fractures. Other diseases which result from alterations in bone resorption include, but are not limited to, Paget""s Disease, primary and secondary hyperparathyroidism, humoral hypercalcemia of malignancy, various cancers where resorption is increased, and rheumatoid arthritis.
Because of the serious disorders that may result from a metabolic imbalance, researchers have been interested in studying bone metabolism, specifically the mechanism by which bone resorption and formation occurs, to ultimately develop a strategy for inhibiting resorption, and/or for improving bone mass and/or bone micro-architecture by stimulating osteoblast activity. However, the action of both osteoclasts and osteoblasts is controlled by a number of complex factors, and thus developing selective therapeutics has proven to be a difficult task.
One approach that has been taken for the development of novel therapeutics for bone disorders is inhibition of the osteoclast proton pump. It has been previously demonstrated that this proton pump is a vacuolar H+-ATPase (see, Blair et al., Science 1989, 245, 855-857; Finbow et al., Biochem. J. 1997, 324, 697-712; Forgac, M. Soc. Gen. Physiol. Ser. 1996, 51, 121-132). It has been shown that osteoclasts, to effect bone resorption, ultimately lower the pH in the sealed microcompartment which underlies their site of attachment to the bone surface (see, Baron et al., J. Cell. Biol. 1985, 101, 2210-2222), thus resulting in the acidic envionment required to dissolve the bone mineral and to allow degradation of the bone matrix by proteases. The osteoclast uses a proton pump (an ATP-dependent transport of protons) to achieve this acidification and thus any therapeutic inhibition of the osteoclast proton pump should lead to a decrease in bone loss or turnover. As a result, many novel therapeutics developed to reduce bone resorption have focused on the inhibition of the proton pump to prevent osteoclast activity and excessive bone resorption. For a discussion of the vacuolar H+-ATPase and inhibitors of vacuolar H+-ATPase see Farina et al., Exp. Opin. Ther. Patents 1999, 9, 157-168 and David, P. and Baron, R. xe2x80x9cThe Vacuolar H+-ATPase: A Potential Target for Drug Development in Bone Diseasesxe2x80x9d Exp. Opin. Invest. Drugs 1995, 4, 725-740.
A wide variety agents that are capable of inhibiting the action of V-ATPases have been disclosed recently. For example, it has been found that Bafilomycin Al, a macrolide antibiotic, can inhibit the V-type H+-ATPases at nanomolar concentrations, and thus is the most potent inhibitor of V-ATPases yet described. One major concern relating to the use of this therapeutic, as well as other derivatives representative of this family of compounds, such as concanamicin, (see, U.S. Pat. No. 5, 610, 178 xe2x80x9cMacrolides and the Use Thereofxe2x80x9d) however, is that it is not capable of specifically inhibiting bone resorption without affecting all other V-ATPases in the body, and thus leads to systemic alteration of cellular physiology and high toxicity. Other therapeutics, such as N-ethylmaleimide, have also proven to be effective inhibitors of V-ATPases, however there is also the concern that these agents may affect other V-type H+-ATPases in vivo. Additionally, gallium and group III metals, nitrate, vanadate, omeprazole and related compounds, WY 47766, S238, and bisphopshonates have also demonstrated inhibition of the osteoclast proton pump, although less effectively or with adverse side effects (see, Baron et al. Exp. Opin. Invest. Drugs 1995, 4, 725 and Farina et al. Exp. Opin. Ther. Patents 1999, 9, 157-168).
Clearly, although progress has been made towards developing therapeutic agents for osteoporosis and other bone disorders, there remains a need to develop potent and selective agents having minimal side effects. In particular, there remains a need to develop selective inhibitors of the osteoclast proton pump.
The present invention provides compounds comprising a bone targeting moiety and a payload and methods for the prevention and/or treatment of bone disorders and/or other related conditions using these compounds or pharmaceutical compositions thereof. In general, the compounds of the present invention comprise a bone targeting moiety and a payload capable of effecting inhibition of the osteoclast proton pump.
Thus, in one aspect, the present invention provides compounds of Formula (I): 
wherein X1 is CH or N;
wherein R1, R2, R3, and R4 are each independently hydrogen, lower alkyl, halogen, hydroxy, alkyloxy, aryl, aryloxy, heteroaryl, trifluoromethoxy, cyano, nitro, thio, alkylthio or a bone targeting moiety, wherein said bone targeting moiety is selected from any one of i-xx: 
wherein each occurrence of M is independently CV2, xe2x80x94NVxe2x80x94, xe2x80x94Oxe2x80x94or xe2x80x94Sxe2x80x94, wherein each occurence of V is independently hydrogen, OH, halogen, or aliphatic; each occurrence of Y is independently a covalent bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94or N(Rj)2, wherein Rj, for each occurrence, is is independently hydrogen, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl; each occurrence of x is independently 0-6, and for compounds i-vi, xi, and xvii, x may preferably be 1-6; wherein L is xe2x80x94(Ch2)pxe2x80x94Hexe2x80x94(CH2)nxe2x80x94, wherein He is absent or is NR"", O or S, wherein R"" is hydrogen or lower alkyl, n is 0-5, and p is 0-5, except when He is absent, the sum of n and p is 1-5; wherein L2 is N or CRK, wherein RK is hydrogen, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl; and wherein each occurrence of R5 is independently hydrogen or lower alkyl, with the proviso that if either of R2 or R4 are bone targeting moieties, He, for the bone targeting moiety at R2 or R4 , is NR"", O, or S, wherein R"" is hydrogen or lower alkyl; wherein R13 represents 0-3 substituents selected from hydrogen, halogen, lower alkyl, lower alkenyl, aryl, heteroaryl, carbonyl, thiocarbonyl, ketone, aldehyde, amino, acylamino, amido, amidino, cyano, nitro, azido, sulfonyl, sulfoxido, sulfate, sulfonate, sulfamoyl, sulfonamido, phosphoryl, phosphorothioate, phosphonate, phosphinate, xe2x80x94(CH2)t-alkyl-, xe2x80x94(CH2)t-alkenyl-, (CH2)talkynyl-, xe2x80x94(CH2)taryl-, xe2x80x94(CH2)taralkyl-, xe2x80x94(CH2)tOHxe2x80x94, xe2x80x94(CH2)tO-lower alkyl-, (CH2)t)-lower alkenyl, xe2x80x94O(CH2)tR, xe2x80x94(CH2)tS-lower alkyl, xe2x80x94(CH2)tS-lower alkenyl, xe2x80x94S(CH2)tR, xe2x80x94(CH2)tNR2, (CH2)tNR-lower alkyl, xe2x80x94(CH2)tNR-lower alkenyl, xe2x80x94NR(CH2)tR, or protected forms of the above, and wherein t is 1-10;
wherein Hc is: 
wherein R6, R7, R9, R10, R11, and R12 are each independently selected from the group consisting of bone targeting moiety as described above, hydrogen, lower alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or wherein R6 and R7 taken together, or any one of R11 and R12, R10 and R11, and R9 and R10 taken together, comprise a substituted or unsubstituted aryl, heteroaryl, or cycloalkyl moiety, wherein said substituted or unsubstituted aryl, heteroaryl, or cycloalkyl moiety is a single ring or is polycyclic; and wherein wherein X2 comprises NR8 or S, wherein R8 is hydrogen, lower alkyl, substituted or unsubstitued aryl, or substituted or unsubstituted heteroaryl; and
whereby at least one of R1-R4 or R6, R7, R9-R12 is substituted with a bone targeting moiety as described above.
In certain embodiments of the compounds as described above, at least one occurrence of Y is O. In certain other embodiments of the compounds as described above, each occurrence of Y is O.
In certain embodiments for compounds as described above, R6 and R7 taken together comprise a substituted or unsubstituted aryl, heteroaryl, or cycloalkyl moiety, and said aryl, heteroaryl, or cycloalkyl moiety is a substituted single or polycyclic ring. In certain other embodiments, substituted single or polycyclic ring is substituted with methyl or alkoxy.
In other embodiments, the present invention provides compounds as described above, wherein the bone targeting moiety comprises a structure of formula (II) 
wherein n is 0-5; wherein L"" is xe2x80x94(CH2)pxe2x80x94Hexe2x80x94, and He is absent or is NR"", O, or S, wherein R"" is hydrogen or lower alkyl, and p is 0-5, except when He is absent, the sum of n and p is 1-5, with the proviso that if either of R2 or R4 are bone targeting moieties, He, for the bone targeting moiety for R2 or R4 , is NR"", O, or S, wherein R"" is hydrogen or lower alkyl; wherein Y is (CH2)q, wherein q is 1-3, or NH; and wherein Z is PO(OR14)2, SO2(OR14), or COOR14, wherein each occurence of R14 is independently hydrogen or lower alkyl.
In still other embodiments, R1, R3 and R4 are each hydrogen; R2 is a bone targeting moiety of formula (II); p is O and He is either NR"", wherein R"" is hydrogen or lower alkyl, or O; wherein He is 
wherein X2 is NH, and R6 and R7 taken together comprise a pyridyl group; wherein Y is CH2 or NH; wherein Z is PO(OR14)2; and wherein R14 is hydrogen or lower alkyl.
In certain other embodiments, R1 and R3 are each hydrogen; wherein R4 is alkoxy; R4 is alkoxy; R2 is a bone targeting group of formula (II); p is O and He is NR"", wherein R"" is hydrogen or lower alkyl, or O; wherein X1 is CH; wherein He is 
wherein X2 is NH; and R6 and R7 taken together comprise a pyridyl group; wherein Y is CH2 or NH; and wherein Z is PO(OR14)2, and R14 is hydrogen or lower alkyl.
In still other embodiments, R1 and R3 are each independently a lower alkyl or hydrogen; R4 is hydrogen; R2 is bone targeting moiety of formula (II); p is O and He is NR"", wherein R""is hydrogen or lower alkyl, or O; wherein X1 is N; wherein Hc is 
wherein X2 is NH; wherein R6 and R7 taken together comprises a substituted or unsubstituted phenyl group; wherein Y is CH2 or NH; and wherein Z is PO(OR14)2, and R14 is hydrogen or lower alkyl. In certain embodiments said phenyl group is substituted with an electron donating moiety.
In another aspect, the present invention provides pharmaceutical compositions comprising any one of the compounds of the present invention and a pharmceutically acceptable carrier or excipient.
In yet another aspect, the present invention provides a method for the treatment and/or prophylaxis of a disease or secondary condition associated with overactivity of osteoclasts in mammals which method comprises the administration of an effective non-toxic amount of a selective inhibitor of mammalian osteoclasts to a patient in need. In certain preferred embodiments, this selective inhibitor of mammalian osteoclasts inhibits the osteoclast proton pump mechanism. While the treatment of any disease or condition associated with the overactivity of osteoclasts is contemplated by the method of the present invention, it is preferred that the disease or secondary condition is selected from the group consisting of osteoporosis, Paget""s Disease, hypercalcemia, rheumatoid arthritis, cancer, metastatic bone destruction, and immune disorder.
As mentioned above, this invention provides a novel class of bone targeted compounds useful for the treatment and/or prevention of metabolic bone disorders, preferably by inhibition of bone resorption, and more preferably by inhibition of bone resorption resulting from inhibition of the osteoclast proton pump. Compounds of this invention comprise those of Formula I, set forth herein, and are illustrated in part by the various classes, subgenera and subsets of compounds described above, and by the various subgenera and species disclosed elsewhere in the specification, claims and figures. It will be appreciated that the inventive compounds may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers.
Also included are pharmaceutically acceptable derivatives of the foregoing compounds, where the phrase xe2x80x9cpharmaceutically acceptable derivativexe2x80x9d denotes any pharmaceutically acceptable salt, ester, or salt of such ester, of such compound, or any other adduct or derivative which, upon administration to a patient, is capable of providing (directly or indirectly) a compound as otherwise described herein, or a metabolite or residue thereof, preferably one which is capable of inhibiting bone resorption. Pharmaceutically acceptable derivatives thus include among others pro-drugs. A pro-drug is a derivative of a compound, usually with significantly reduced pharmacological activity, which contains an additional moiety which is susceptible to removal in vivo yielding the parent molecule as the pharmacologically active species. An example of a pro-drug is an ester which is cleaved in vivo to yield a compound of interest. Pro-drugs of a variety of compounds, and materials and methods for derivatizing the parent compounds to create the pro-drugs, are known and may be adapted to the present invention. One technique for providing a prodrug of a compound of the present invention is described generally in Niemi et al., J. Med. Chem. 1999, 42, 5053-5058.
The term xe2x80x9cinhibition of bone resorptionxe2x80x9d or xe2x80x9cbone resorption inhibitingxe2x80x9d, as used herein, means treating or preventing bone resorption by the direct or indirect alteration of osteoclast function or activity. Inhibition of bone resorption refers to treatment or prevention of bone loss, especially the inhibition of removal of existing bone either from the mineral phase and/or the organic matrix phase, through direct or indirect alteration of osteoclast formation or activity. In preferred embodiments, the inhibition of bone resorption is achieved by inhibition of the osteoclast proton pump.
Any of a variety of in vivo or in vitro assays may be employed to assess the ability of inventive compositions to inhibit bones resorption and/or proton pump activity (see, for example, the Exemplification section, which describes a useful rabbit osteoclast assay). In particularly preferred embodiments of the invention, the observed inhibition of bones resorption and/or proton pump activity is selective in that the inventive compositions do not exert significant negative effects on biological processes other than bone resorption. For example, particularly preferred inventive compositive show specific inhibition of the osteoclast proton pump as compared with other proton pumps. In some cases, such specific inhibition may result from specific localization of the inventive composition to osteoclasts, so that compositions delivered in vivo do not have the opportunity to inhibit other proton pumps; in other cases, specific inhibition may be attributed to specific action of the inventive payload on the osteoclast proton pump as compared with other proton pumps.
The term xe2x80x9cpayload,xe2x80x9d in general, includes therapeutic agents (e.g., a small molecule, a drug, a radiotherapeutic atom, etc.), detectable labels (e.g., fluorescent, radioactive, radiopaque, etc.), or any other moiety desired to be delivered to the site of an abnormal condition. In the context of the present invention, particularly preferred payloads include those capable of acting as inhibitors of the osteoclast proton pump.
xe2x80x9cSubjectxe2x80x9d shall mean a human or animal (e.g., rat, mouse, cow, pig, horse, sheep, monkey, cat, dog, goat etc.).
A xe2x80x9ctargetxe2x80x9d shall mean an in vivo site to which targeted agents bind. A target may refer to a molecular structure to which a targeting moiety binds, such as a hapten, epitope, receptor, dsDNA fragment, carbohydrate, or enzyme. Alternatively or additionally, a target may be a type of tissue, e.g., bone. A preferred target is bone. In certain preferred embodiments of the present invention, target cells include osteoclasts.
The term xe2x80x9ctargeting moietyxe2x80x9d refers to any molecular structure which assists the inventive composite in localizing to a particular target area, entering a target cell(s), and/or binding to a target receptor. As described herein, the compounds of the present invention are targeted to bone, and more preferably are osteoclast selective.
A xe2x80x9ctherapeutic agentxe2x80x9d shall mean an agent capable of having a biological effect on a host. Preferred therapeutic agents are capable of preventing or reducing one or more symptoms of a metabolic disorder resulting from overactivity of ostecoclasts. In a preferred embodiment for treating osteoporosis, the therapeutic agent is an inhibitor of the osteoclast proton pump.
A named R group will generally have the structure which is recognized in the art as corresponding to R groups having that name. For the purposes of illustration, representative R groups as enumerated in the specification and claims of the present application are defined herein. These definitions are intended to supplement and illustrate, not preclude, the definitions known to those of skill in the art.
The term xe2x80x9cindependently selectedxe2x80x9d is used herein to indicate that the R groups can be identical or different.
The term xe2x80x9calkylxe2x80x9d refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), and more preferably 20 or fewer. Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
Moreover, the term xe2x80x9calkylxe2x80x9d (or xe2x80x9clower alkylxe2x80x9d) as used throughout the specification, examples, and claims is intended to include both xe2x80x9cunsubstituted alkylsxe2x80x9d and xe2x80x9csubstituted alkylsxe2x80x9d, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphorothioate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphorothioate, phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), xe2x80x94CF3, xe2x80x94CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, xe2x80x94CF3, xe2x80x94CN, and the like.
The term xe2x80x9caralkylxe2x80x9d, as used herein, refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group). Exemplary aralkyl groups include, but are not limited to, benzyl and more generally (CH2)nPh, where Ph is phenyl or substituted phenyl, and n is 1, 2, or 3.
The terms xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.
Unless the number of carbons is otherwise specified, xe2x80x9clower alkylxe2x80x9d as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure. Likewise, xe2x80x9clower alkenylxe2x80x9d and xe2x80x9clower alkynylxe2x80x9d have similar chain lengths. Preferred alkyl groups are lower alkyls. In preferred embodiments, a substituent designated herein as alkyl is a lower alkyl.
The term xe2x80x9carylxe2x80x9d as used herein includes 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as xe2x80x9caryl heterocyclesxe2x80x9d or xe2x80x9cheteroaromatics.xe2x80x9d The aromatic ring can be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, xe2x80x94CF3, xe2x80x94CN, or the like. The term xe2x80x9carylxe2x80x9d also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are xe2x80x9cfused ringsxe2x80x9d) wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
The terms ortho, meta and para apply to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively. For example, the names 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.
The terms xe2x80x9cheterocyclylxe2x80x9d or xe2x80x9cheterocyclic groupxe2x80x9d refer to 3- to 10-membered ring structures, more preferably 3- to 7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can also be polycycles. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, xe2x80x94CF3, xe2x80x94CN, or the like.
The terms xe2x80x9cpolycyclylxe2x80x9d or xe2x80x9cpolycyclic groupxe2x80x9d refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are xe2x80x9cfused ringsxe2x80x9d. Rings that are joined through non-adjacent atoms are termed xe2x80x9cbridgedxe2x80x9d rings. Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, xe2x80x94CF3, xe2x80x94CN, or the like.
The term xe2x80x9ccarbocyclexe2x80x9d, as used herein, refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.
As used herein, the term xe2x80x9cnitroxe2x80x9d means xe2x80x94NO2; the term xe2x80x9chalogenxe2x80x9d designates xe2x80x94F, xe2x80x94Cl, xe2x80x94Br or xe2x80x94I; the term xe2x80x9csulfhydrylxe2x80x9d means xe2x80x94SH; the term xe2x80x9chydroxylxe2x80x9d means xe2x80x94OH; and the term xe2x80x9csulfonylxe2x80x9d means xe2x80x94SO2xe2x80x94.
The terms xe2x80x9caminexe2x80x9d and xe2x80x9caminoxe2x80x9d are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that can be represented by the general formula: 
wherein R9, R10 and Rxe2x80x210 each independently represent a hydrogen, an alkyl, an alkenyl, xe2x80x94(CH2)mxe2x80x94R8, or R9 and R10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R8 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. In preferred embodiments, only one of R9 or R10 can be a carbonyl, e.g., R9, R10 and the nitrogen together do not form an imide. In even more preferred embodiments, R9 and R10 (and optionally Rxe2x80x210) each independently represent a hydrogen, an alkyl, an alkenyl, or xe2x80x94(CH2)mxe2x80x94R8. Thus, the term xe2x80x9calkylaminexe2x80x9d as used herein means an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R9 and R10 is an alkyl group.
The term xe2x80x9cacylaminoxe2x80x9d is art-recognized and refers to a moiety that can be represented by the general formula: 
wherein R9 is as defined above, and Rxe2x80x211 represents a hydrogen, an alkyl, an alkenyl or xe2x80x94(CH2)mxe2x80x94R8, where m and R8 are as defined above.
The term xe2x80x9camidoxe2x80x9d is art recognized as an amino-substituted carbonyl and includes a moiety that can be represented by the general formula: 
wherein R9, R10 are as defined above. Preferred embodiments of the amide will not include imides which may be unstable.
The term xe2x80x9calkylthioxe2x80x9d refers to an alkyl group, as defined above, having a sulfur radical attached thereto. In preferred embodiments, the xe2x80x9calkylthioxe2x80x9d moiety is represented by one of xe2x80x94S-alkyl, xe2x80x94S-alkenyl, xe2x80x94S-alkynyl, and xe2x80x94Sxe2x80x94(CH2)mxe2x80x94R8, wherein m and R8 are defined above. Representative alkylthio groups include methylthio, ethyl thio, and the like.
The term xe2x80x9ccarbonylxe2x80x9d is art recognized and includes such moieties as can be represented by the general formula: 
wherein X is a bond or represents an oxygen or a sulfur, and R11 represents a hydrogen, an alkyl, an alkenyl, xe2x80x94(CH2)mxe2x80x94R8 or a pharmaceutically acceptable salt, Rxe2x80x211 represents a hydrogen, an alkyl, an alkenyl or xe2x80x94(CH2)mxe2x80x94R8, where m and R8 are as defined above. Where X is an oxygen and R11 or Rxe2x80x211 is not hydrogen, the formula represents an xe2x80x9cesterxe2x80x9d. Where X is an oxygen, and R11 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R11 is a hydrogen, the formula represents a xe2x80x9ccarboxylic acidxe2x80x9d. Where X is an oxygen, and Rxe2x80x211 is hydrogen, the formula represents a xe2x80x9cformatexe2x80x9d. In general, where the oxygen atom of the above formula is replaced by sulfir, the formula represents a xe2x80x9cthiolcarbonylxe2x80x9d group. Where X is a sulfur and R11 or Rxe2x80x211 is not hydrogen, the formula represents a xe2x80x9cthiolester.xe2x80x9d Where X is a sulfur and R11 is hydrogen, the formula represents a xe2x80x9cthiolcarboxylic acid.xe2x80x9d Where X is a sulfur and R11xe2x80x2 is hydrogen, the formula represents a xe2x80x9cthiolformate.xe2x80x9d On the other hand, where X is a bond, and R11 is not hydrogen, the above formula represents a xe2x80x9cketonexe2x80x9d group. Where X is a bond, and R11 is hydrogen, the above formula represents an xe2x80x9caldehydexe2x80x9d group.
The terms xe2x80x9calkoxylxe2x80x9d or xe2x80x9calkoxyxe2x80x9d as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. An xe2x80x9cetherxe2x80x9d is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of xe2x80x94O-alkyl, xe2x80x94O-alkenyl, xe2x80x94O-alkynyl, xe2x80x94Oxe2x80x94(CH2)mxe2x80x94R8, where m and R8 are described above.
The term xe2x80x9csulfonatexe2x80x9d is art recognized and includes a moiety that can be represented by the general formula: 
in which R41 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.
The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively. The terms triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, p-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.
The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively. A more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations. The abbreviations contained in this list, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference.
The term xe2x80x9csulfatexe2x80x9d is art recognized and includes a moiety that can be represented by the general formula: 
in which R41 is as defined above.
The term xe2x80x9csulfonamidoxe2x80x9d is art recognized and includes a moiety that can be represented by the general formula: 
in which R9 and Rxe2x80x211 are as defined above.
The term xe2x80x9csulfamoylxe2x80x9d is art-recognized and includes a moiety that can be represented by the general formula: 
in which R9 and R10 are as defined above.
The term xe2x80x9csulfonylxe2x80x9d, as used herein, refers to a moiety that can be represented by the general formula: 
in which R44 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
The term xe2x80x9csulfoxidoxe2x80x9d as used herein, refers to a moiety that can be represented by the general formula: 
in which R44 is selected from the group consisting of hydrogen, alky, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl.
A xe2x80x9cphosphorylxe2x80x9d can in general be represented by the formula: 
wherein Q1 represented S or O, and R46 represents hydrogen, a lower alkyl or an aryl. When used to substitute, e.g., an alkyl, the phosphoryl group of the phosphorylalkyl can be represented by the general formula: 
wherein Q1 represents S or O, and each R46 independently represents hydrogen, a lower alkyl or an aryl, Q2 represents O, S or N. When Q is an S, the moiety is a xe2x80x9cphosphorothioatexe2x80x9d.
As used herein, the definition of each expression, e.g. alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
It will be understood that xe2x80x9csubstitutionxe2x80x9d or xe2x80x9csubstituted withxe2x80x9d includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
As used herein, the term xe2x80x9csubstitutedxe2x80x9d is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
The phrase xe2x80x9cprotecting groupxe2x80x9d as used herein means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991, incorporated herein by reference).
Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, where only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomer ratios are all contemplated by the present invention. Those of ordinary skill in the art will readily appreciate that analogous ratios are contemplated for more complex isomer mixtures.
If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
Contemplated equivalents of the compounds described above include compounds which otherwise correspond thereto, and which have the same general properties thereof (e.g., bone targeting agents), wherein one or more simple variations of substituents are made which do not adversely affect the efficacy of the compound in targeting bone. In general, the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here.
For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.